Antibody-drug conjugates (ADCs) are a class of therapeutics that combines the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules. The use of ADC empowers the cancer killing activity of antibody by conjugated cytotoxic agents, while target-specific delivery avoids systemic toxicity caused by exposure to free toxic agents. As of May 2014, two ADCs have been approved by FDA for treating human cancers. Adcetris (Brentuximab vedotin or SGN-35), an anti-CD30 antibody conjugated with cytotoxic agent MMAE, is designed to treat CD30-positive relapsing lymphoma. Kadcyla (T-DM1), an anti-HER2 antibody conjugated with cytotoxic agent DM1, is designed to treat HER2-positive metastatic breast cancer.
The linker technology profoundly impacts ADC potency, specificity, and safety. Enzyme-labile linkers utilize the differential activities of proteases inside and outside of the cells to achieve control of the drug release. A drug can be conjugated to antibody via peptide bond, and can only be specifically cleaved by the action of lysosomal proteases present inside the cells, and at elevated levels in certain tumor types (Koblinski et al (2000) Clin. Chem. Acta 291:113-135). This ensures the stability of linker in the blood stream to limit the damage to healthy tissue. However, the increased hydrophobicity of some enzyme-labile linkers can lead to aggregation of ADC, particularly with strongly hydrophobic drugs. A hydrophilic self-immolative linker may provide better serum stability via specific enzyme-labile design, as well as achieve better efficacy via bystander effect on the heterogeneous cancer cells.
Folate receptor alpha (FRA), a membrane protein, which binds folic acid with high affinity and mediates the cellular uptake of folate via receptor-mediated endocytosis (Leamon et al., 1991, PNAS 88:5572-5576). Overexpression of FRA was found in 90% epithelial ovarian cancers, as well as numerous other cancers including endometrial cancer, kidney cancer, lung cancer, mesothelioma, breast cancer, brain cancer, and myeloid leukemia, whereas most normal tissues express low to negligible levels (Coney et al., 1991, Cancer Res. 51:6125-6132). The differential expression profiles of FRA in cancer versus normal tissues warrant the development of Ab-based therapeutics. A humanized form of the murine monoclonal anti-FRA antibody was shown effective in preclinical studies (Ebel et al., 2007, Cancer Immun 7:1-8), and is currently being evaluated in patients with FRA expressing tumors (Kalli et al., 2007, Curr Opin Investig 8:1067-1073). Furthermore, the ability of FRA to mediate endocytosis makes it an attractive candidate for the development of cancer-targeting ADC. To date, various drug conjugates and anti-FRA antibodies are being tested in clinical trials and have demonstrated safety (Xia et al., 2010, J Med Chem. 53:6811-6824; Zacchetti et al., 2009, Nucl Med Biol. 36: 759-770).
There is a need for anti-cancer therapeutics having improved efficacy that can deliver cytotoxic drugs to cancer cells through an antibody-drug conjugate (ADC) format.